Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

The rise of nanotoxicology: A successful collaboration between engineering and biology

Department of Chemical and Materials Engineering, University of Dayton, 300 College Park, Dayton, OH 45469, USA

The field of nanotechnology has grown exponentially in the last decade, due to increasing capabilities in material science which allows for the precise and reproducible synthesis of nanomaterials (NMs). However, the unique physicochemical properties of NMs that make them attractive for nanotechnological applications also introduce serious health and safety concerns; thus giving rise to the field of nanotoxicology. Initial efforts focused on evaluating the toxic potential of NMs, however, it became clear that due to their distinctive characteristics it was necessary to design and develop new assessment metrics. Through a prolific collaboration, engineering practices and principles were applied to nanotoxicology in order to accurately evaluate NM behavior, characterize the nano-cellular interface, and measure biological responses within a cellular environment. This review discusses three major areas in which the field of nanotoxicology progressed as a result of a strong engineering-biology partnership: 1) the establishment of standardized characterization tools and techniques, 2) the examination of NM dosimetry and the development of mathematical, predictive models, and 3) the generation of physiologically relevant exposure systems that incorporate fluid dynamics and high-throughput mechanisms. The goal of this review is to highlight the multidisciplinary efforts behind the successes of nanotoxicology and celebrate the partnerships that have emerged from this research field.
  Article Metrics

Keywords nanotoxicology; dosimetry; characterization; in vitro exposure models

Citation: Kristen K. Comfort. The rise of nanotoxicology: A successful collaboration between engineering and biology. AIMS Bioengineering, 2016, 3(3): 230-244. doi: 10.3934/bioeng.2016.3.230


  • 1. Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113: 823-839.    
  • 2. Kessler R (2011) Engineered nanoparticles in consumer products: understanding a new ingredient. Environ Health Perspect 119: 120-125.    
  • 3. Vance ME, Kuiken T, Vejerano EP, et al. (2015) Nanotechnology in the real world: redeveloping the nanomaterial consumer products inventory. Beilstein J Nanotechnol 6: 1769-1780.    
  • 4. Comfort KK, Maurer EI, Braydich-Stolle LK, et al. (2011) Interference of silver, gold, and iron oxide nanoparticles on epidermal growth factor signal transduction in epithelial cells. ACS Nano 5: 10000-10008.    
  • 5. Dowding JM, Das S, Kumar A, et al. (2013) Cellular interaction and toxicity depend on physicochemical properties and surface modification of redox-active nanomaterials. ACS Nano 7: 4855-4868.    
  • 6. Hussain SM, Warheit DB, Ng SP, et al. (2015) At the crossroads of nanotoxicology in vitro: past achievements and current challenges. Toxicol Sci 147: 5-16.
  • 7. Brunelli A, Pojana G, Callegaro S, et al. (2013) Agglomeration and sedimentation of titanium dioxide nanoparticles (n-TiO2) in synthetic and real waters. J Nanopart Res 15: 1684.    
  • 8. Cho EC, Zhang Q, Xia G (2011) The effect of sedimentation and diffusion on cellular uptake of gold nanoparticles. Nat Nanotechnol 6: 385-391.    
  • 9. Braydich-Stolle LK, Breitner EK, Comfort KK, et al. (2014) Dynamic characteristics of silver nanoparticles in physiological fluids: toxicological implications. Langmuir 30: 15309-15316.    
  • 10. Hinderliter PM, Minard KR, Orr G, et al. (2010) ISDD: a computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies. Part Fibre Toxicol 7: 36.    
  • 11. Maurer-Jones MA, Mousavi MPS, Chen LD, et al. (2013) Characterization of silver ion dissolution from silver nanoparticles using fluorous-phase ion-selective electrodes and assessment of resultant toxicity to Shewanella oneidensis. Chem Sci 4: 2564-2572.    
  • 12. Bian SW, Mudunkotuwa IA, Rupasinghe T, et al. (2011) Aggregation and dissolution of 4 nm ZnO nanoparticles in aqueous environments: influence of pH, ionic strength, size, and adsorption of humic acid. Langmuir 27: 6059-6068.    
  • 13. Braun NJ, DeBrosse MC, Hussain SM, et al. (2016) Modification of the protein corona-nanoparticle complex by physiological factors. Mat Sci Eng C 64: 34-42.    
  • 14. Ong KJ, MacCormack TJ, Clark RJ, et al. (2014) Widespread nanoparticle-assay interference: implications for nanotoxicity testing. PLoS One 9: e90650.    
  • 15. Worle-Knirsch JM, Pulskamp K, Krug HF (2012) Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6: 1261-1268.
  • 16. Liang L, Cui M, Zhang M, et al. (2015) Nanoparticles’ interference in the evaluation of in vitro toxicity of silver nanoparticles. RSC Adv 5: 67327-67334.    
  • 17. Gatoo MA, Naseem S, Arfat MY, et al. (2014) Physiochemical properties of nanomaterials: implication in associated toxic manifestations. Biomed Res Int 2014: 498420.
  • 18. Griffitt RJ, Luo J, Gao J, et al. (2008) Effects of particle composition and species on toxicity of metallic nanomaterials in aquatic organisms. Environ Toxicol Chem 27: 1972-1978.    
  • 19. Shang L, Nienhaus K, Nienhaus GU (2014) Engineered nanoparticles interacting with cells: size matters. J Nanobiotechnol 12: 5.    
  • 20. Hauck TS, Ghazani AA, Chan WCW (2008) Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small 4: 153-159.    
  • 21. Yu T, Greish K, McGill LD, et al. (2012) Influence of geometry, porosity, and surface characteristics of silica nanoparticles on acute toxicity: their vasculature effect and tolerance threshold. ACS Nano 6: 2289-2301.    
  • 22. Zhu ZJ, Wang H, Yan B, et al. (2012) Effect of surface charge on uptake and distribution of gold nanoparticles in four plant species. Environ Sci Technol 46: 12391-12398.    
  • 23. Misra SK, Nuseibeh S, Dybowska A, et al. (2014) Comparative study using spheres, rods and spindle-shaped nanoplatelets on dispersion stability, dissolution, and toxicity of CuO nanomaterials. Nanotoxicology 8: 422-432.    
  • 24. Jana NR, Gearheart LA, Obare SO, et al. (2002) Liquid crystalline assemblies of ordered gold nanorods. J Mat Chem 12: 2909-2912.    
  • 25. Gil PR, Oberdorster G, Elder A, et al. (2010) Correlating physico-chemical and toxicological properties of nanoparticles: the present and the future. ACS Nano 5: 5527-5531.
  • 26. Bouwmeester H, Lynch I, Marvin HJ, et al. (2011) Minimal analytical characterization of engineered nanomaterials needed for hazard assessment in biological matrices. Nanotoxicology 5: 1-11.    
  • 27. Baer D, Gaspar DJ, Nachimuthu P et al. (2010) Application of surface chemistry analysis tools for characterization of nanoparticles. Anal Bioanal Chem 396: 983-1002.    
  • 28. Lin PC, Lin S, Sridhar R (2013) Techniques for physicochemical characterization of nanomaterials. Biotechnol Adv 32: 711-726.
  • 29. Braun NJ, Comfort KK, Schlager JJ, et al. (2013) Partial recovery of silver nanoparticle-induced neural cytotoxicity through the application of a static magnetic field. Bionanoscience 3: 367-377.    
  • 30. Baalousha M, Ju-Nam Y, Cole PA, et al. (2012) Characterization of cerium oxide nanoparticles-part 1: size measurements. Environ Toxicol Chem 31: 983-993.    
  • 31. Joshi M, Bhattacharyya A, Ali SW (2008) Characterization techniques for nanotechnology applications in textiles. Ind J Fibre Text Res 33: 304-317.
  • 32. Pachauri T, Singla V, Satsangi A, et al. (2013) SEM-EDX characterization of individual coarse particles in Agra, India. Aerosol Air Qual Res 13: 523-536.
  • 33. Murdock RC, Braydich-Stolle L, Schrand AM, et al. (2008) Characterization of nanomaterial dispersion in solution prior to in vitro exposure using dynamic light scattering technique. Toxicol Sci 10: 239-253.
  • 34. Breitner EK, Hussain SM, Comfort KK (2015) The role of biological fluid and dynamic flow in the behavior and cellular interactions of gold nanoparticles. J Nanobiotechnol 13:56.    
  • 35. Untener EA, Comfort KK, Maurer EI, et al. (2013) Tannic acid coated gold nanorods demonstrate a distinctive form of endosomal uptake and unique distribution within cells. ACS Appl Mat Interfaces 5: 8366-8373.    
  • 36. Sethi M, Joung G, Knecht MR (2009) Stability and electrostatic assembly of Au nanorods for use in biological assays. Langmuir 25: 317-325.    
  • 37. Dablemont C, Lang P, Mangeney C, et al. (2008) FTIR and XPS study of Pt nanoparticle functionalization and interaction with alumina. Langmuir 24: 5832-5841.    
  • 38. Klapetek P, Valtr M, Necas D, et al. (2010) Atomic force microscopy analysis of nanoparticles in non-ideal conditions. Nanoscale Res Lett 6: 514.
  • 39. Elzey S, Grassian VH. (2010) Agglomeration, isolation and dissolution of commercially manufactured silver nanoparticles in aqueous environments. J Nanopart Res 12: 1945-1958.    
  • 40. Woehl TJ, Park C, Evans JE, et al. (2014) Direct observation of aggregative nanoparticle growth: kinetic modeling of the size distribution and growth rate. Nano Lett 14: 373-378.    
  • 41. Comfort KK, Maurer EI, Hussain SM (2014) Slow release of ions from internalized silver nanoparticles modifies the epidermal growth factor signaling response. Coll Surf B Biointerface 123: 136-142.    
  • 42. Comfort KK, Braydich-Stolle LK, Maurer EI, et al. (2014) Less is more: in vitro chronic, low-level nanomaterial exposure provides a more meaningful toxicity assessment. ACS Nano 8: 3260-3271.    
  • 43. Gardner JW (2002) Death by water intoxication. Mil Med 167.5: 432-434.
  • 44. DeBrosse MC, Comfort KK, Untener EA, et al. (2013) High aspect ratio gold nanorods displayed augmented cellular internalization and surface mediated cytotoxicity. Mat Sci Eng C 33: 4094-4100.    
  • 45. Luby AO, Breitner EK, Comfort KK (2015) Preliminary protein corona formation stabilizes gold nanoparticles and improves deposition efficiency. Appl Nanosci doi: 10.1007/s13204-015-0501-z.
  • 46. Fabricius AL, Duester L, Meermann et al. (2014) ICP-MS based characterization of inorganic nanoparticles-sample preparation and off-line fractionation strategies. Anal Bioanal Chem 406: 467-479.    
  • 47. Xiao Y, Vijver MG, Chen G, et al. (2015) Toxicity and accumulation of Cu and ZnO nanoparticles in Daphnia magna. Environ Sci Technol 49: 4657-4664.    
  • 48. Sabella S, Carney RP, Brunetti V, et al. (2014) A general mechanism for intracellular toxicity of metal-containing nanoparticles. Nanoscale 6: 7052-7061.    
  • 49. Comfort KK, Maurer EI, Hussain SM (2013) The biological impact of concurrent exposure to metallic nanoparticles and a static magnetic field. Bioelectromagnetics 24: 500-511.
  • 50. Maurer EI, Comfort KK, Hussain SM, et al. (2012) Novel platform development using an assembly of carbon nanotube, nanogold and immobilized RNA capture element towards rapid, selective sensing of bacteria. Sensors 12: 8135-8144.    
  • 51. Kempen PJ, Hitzman C, Sasportas LS, et al. (2013) Advanced characterization techniques for nanoparticles for cancer research: applications of SEM and NanoSIMS for locating Au nanoparticles in cells. Mater Res Soc Symp Proc 1569: 157-163.
  • 52. DeVolder MF, Tawfick SH, Baughman RH, et al. (2013) Carbon nanotubes: present and future commercial applications. Science 339: 535-539.    
  • 53. Marangon I, Boggetto N, Menard-Moyon C, et al. (2013) Localization and relative quantification of carbon nanotubes in cells with multispectral imaging flow cytometry. J Vis Exp 82: e50566.
  • 54. Chilek JL, Wang R, Draper RK, et al. (2014) Use of gel electrophoresis and Raman spectroscopy to characterize the effect of the electronic structure of single-wall carbon nanotubes on cellular uptake. Anal Chem 86: 2882-2887.    
  • 55. DeLoid G, Cohen JM, Dark R, et al. (2014) Estimating the effective density of engineered nanomaterials for in vitro dosimetry. Nat Commun 5: 3514.
  • 56. Teeguarden JG, Hinderliter PM, Orr G, et al. (2007) Particokinetics in vitro: dosimetry considerations for in vitro nanoparticle toxicity assessments. Toxicol Sci 95: 300-312.
  • 57. Comfort KK, Speltz J, Stacy BM, et al. (2013) Physiological fluid specific agglomeration patterns diminish gold nanorod photothermal characteristics. Adv Nanopart 2: 336-343.    
  • 58. Son J, Vavra J, Forbes VE (2015) Effects of water quality parameters on agglomeration and dissolution of copper oxide nanoparticles (CuO-NPs) using a central composite circumscribed design. Sci Total Environ 521: 183-190.
  • 59. Stacy BM, Comfort KK, Comfort DA, et al. (2013) In vitro identification of gold nanorods through hyperspectral imaging. Plasmonics 8: 1235-1240.    
  • 60. Khanbeig A, Kuman A, Sadouki F et al. (2012) The delivered dose: applying particokinetics to in vitro investigations of nanoparticle internalization by macrophages. J Control Release 162: 259-266.    
  • 61. Cohen J, DeLoid G, Pyrgiotakis G, et al. (2013) Interactions of engineered nanomaterials in physiological media and implications for in vitro dosimetry. Nanotoxicology 7: 417-431.    
  • 62. Cohen JM, Teeguarde JG, Demokritou P (2014) An integrated approach for the in vitro dosimetry of engineered nanomaterials. Part Fibre Toxicol 11:20.    
  • 63. Summers MRB, Brown MR, Hondow N, et al. (2015) Statistical prediction of nanoparticle delivery: from cell culture media to cell. Nanotechnology 26: 155101.
  • 64. Liu R, Liu HH, Ji Z, et al. (2015) Evaluation of toxicity ranking for metal oxide nanoparticles via an in vitro dosimetry model. ACS Nano 9: 9303-9313.    
  • 65. Richarz AN, Madden JC, Robinson RLM, et al. (2015) Development of computational models for the prediction of the toxicity of nanomaterials. Perspect Sci 3: 27-29.    
  • 66. Burello E, Worth AP (2011) QSAR modeling of nanomaterials. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3: 298-306.    
  • 67. Puzyn T, Rasulev B, Gajewicz A, et al. (2011) Using nano-QSAR to predict the cytotoxicity of metal oxide nanoparticles. Nat Nanotechnol 6: 175-178.    
  • 68. Desai T, Keblinski P, Kumar SK (2005) Molecular dynamics simulations of polymer transport in nanocomposites. J Chem Phys 122: 134910.    
  • 69. Song Z, Wang Y, Xu Z (2015) Mechanical responses of the bio-nano interface: a molecular dynamics study of graphene-coated lipid membrane. Theor Appl Mech Lett 5: 231-235.    
  • 70. Arora S, Rajwade JM, Paknikar KM (2012) Nanotoxicology and in vitro studies: the need of the hour. Toxicol Appl Pharmacol 258: 151-165.    
  • 71. Demokritou P, Gass S, Pyrgiotakis G, et al. (2013) An in vivo and in vitro toxicological characterization of realistic nanoscale CeO2 inhalation exposures. Nanotoxicology 7: 1338-1350.    
  • 72. Frohlich E, Salar-Behzadi S (2014) Toxicological assessment of inhaled nanoparticles: role of in vivo, ex vivo, and in silico studies. Int J Mol Sci 15: 4795-4822.    
  • 73. Voight N, Henrich-Noach P, Kockentiedt S, et al. (2014) Toxicity of polymeric nanoparticles in vivo and in vitro. J Nanopart Res 6: 1-13.
  • 74. Cho WS, Duffin R, Howie SEM, et al. (2011) Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol 8: 27.    
  • 75. Shacter E, Weitzman SA (2002) Chronic inflammation and cancer. Oncology 16: 230-232.
  • 76. Kusek ME, Pazos MA, Pirazi W, et al. (2014) In vitro coculture to assess pathogen induced neutrophil trans-epithelial migration. J Vis Exp 6: e50823
  • 77. Walczak AP, Kramer E, Hendriksen PJ, et al. (2015) In vitro gastrointestinal digestion increases the translocation of polystyrene nanoparticles in an in vitro intestinal co-culture model. Nanotoxicology 9:886-894.    
  • 78. Fede C, Fortunati I, Weber V, et al. (2015) Evaluation of gold nanoparticles toxicity toward human endothelial cells under static and flow conditions. Microvas Res 97:147-155.    
  • 79. Ucciferri N, Collnot EM, Gaiser BK, et al. (2014) In vitro toxicology screening of nanoparticles on primary human endothelial cells and the role of flow in modulating cell response. Nanotoxicology 8: 697-708.    
  • 80. Jeannnet N, Fierz M, Klaberer M, et al. (2015) Nano aerosol chamber for in vitro toxicity (NACIVT) studies. Nanotoxicology 9: 34-42.    
  • 81. Xie Y, Williams NG, Tolic A, et al. (2012) Aerosolized ZnO nanoparticles induce toxicity in alveolar type II epithelial cells at the air-liquid interface. Toxicol Sci 125: 450-461.
  • 82. Macarron R, Banks MN, Bojanic D, et al. (2011) Impact of high-throughput screening in biomedical research. Nat Rev Drug Discov 10: 188-195.    
  • 83. Mahto SK, Charwat V, Rothen-Rutishauser B, et al. (2015) Microfluidic platforms for advanced risk assessments of nanomaterials. Nanotoxicology 9: 381-395.    
  • 84. Oberdӧrster G, Maynard A, Donaldson K, et al. (2005) Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol 2: 8.    
  • 85. Esch E, Bahinksi A, Huh D (2014) Organs-on-chip at the frontiers of drug discovery. Nat Rev Drug Discov 14: 248-260.    


Reader Comments

your name: *   your email: *  

Copyright Info: 2016, Kristen K. Comfort, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved